The voltage-gated sodium channel is a large integral membrane protein complex present in neurons and excitable tissues where it contributes to processes such as membrane excitability and muscle contraction (Ogata et al., Jpn. J. Pharmacol. (2002) 88(4) 365-77), and has been identified as a primary target for the treatment of pain. Genes encoding for nine distinct mammalian isoforms of NaV channels (NaV isoforms 1.1-1.9) have been sequenced. Variation in the gating properties of different NaV isoforms, cellular distributions, and expression levels influence the physiology of nerve cell conduction. A mounting body of evidence suggests that individual NaV isoforms NaV 1.3, 1.7, and 1.8 are disproportionately involved in pain signaling and nociception, and that an isoform-specific inhibitor of NaV could provide pain relief without the accompanying undesirable effects of a non-specific NaV antagonist or an opioid drug (Momin et al., Curr Opin Neurobiol. 18(4): 383-8, 2008; Rush et al., J. Physiol. 579(Pt 1): 1-14, 2007).
Recently, a human genetic disorder resulting in a loss of function mutation in NaV 1.7 has been correlated with congenital insensitivity to pain (Cox et al., Nature. (2006) 444(7121) 894-898). The design of a drug which selectively inhibits NaV 1.7 over the other NaV channels is therefore desirable. Such a drug design is challenging given the high structural homology (75-96%) of the mammalian NaV isoforms. There exists a need for compounds which selectively inhibit NaV 1.7 over other NaV isoforms.